Mahdi Ramsan

Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial

BACKGROUND Anaemia caused by iron deficiency is common in children younger than age 5 years in eastern Africa. However, there is concern that universal supplementation of children with iron and folic acid in areas of high malaria transmission might be harmful. METHODS We did a randomised, placebo-controlled trial, of children aged 1-35 months and living in Pemba, Zanzibar. We assigned children to daily oral supplementation with: iron (12.5 mg) and folic acid (50 mug; n=7950), iron, folic acid, and zinc (n=8120), or placebo (n=8006); children aged 1-11 months received half the dose. Our primary endpoints were all-cause mortality and admission to hospital. Analyses were by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59549825. FINDINGS The iron and folic acid-containing groups of the trial were stopped early on Aug 19, 2003, on the recommendation of the data and safety monitoring board. To this date, 24 076 children contributed a follow-up of 25,524 child-years. Those who received iron and folic acid with or without zinc were 12% (95% CI 2-23, p=0.02) more likely to die or need treatment in hospital for an adverse event and 11% (1-23%, p=0.03) more likely to be admitted to hospital; there were also 15% (-7 to 41, p=0.19) more deaths in these groups. INTERPRETATION Routine supplementation with iron and folic acid in preschool children in a population with high rates of malaria can result in an increased risk of severe illness and death. In the presence of an active programme to detect and treat malaria and other infections, iron-deficient and anaemic children can benefit from supplementation. However, supplementation of those who are not iron deficient might be harmful. As such, current guidelines for universal supplementation with iron and folic acid should be revised.

Efficacy of mebendazole and levamisole alone or in combination against intestinal nematode infections after repeated targeted mebendazole treatment in Zanzibar

OBJECTIVE To evaluate the efficacy of and resistance to mebendazole (500 mg) and levamisole (40 or 80 mg), alone or in combination, for the treatment of Ascaris lumbricoides, Trichuris trichiura and hookworm infections on Pemba Island - an area exposed to periodic school-based mebendazole treatment since 1994. METHODS A randomized, placebo-controlled trial was carried out in 914 children enrolled from the first and fifth grades of primary schools. Stool samples collected at baseline and 21 days after treatment were examined by the Kato-Katz technique to assess the prevalence and intensity of helminth infection. FINDINGS Efficacies of mebendazole and levamisole as single treatments against intestinal nematode infections were comparable with those in previous trials, but mebendazole treatment of hookworm infections gave significantly lower cure (7.6%) and egg reduction (52.1%) rates than reported in a study undertaken before the beginning of periodic chemotherapy (cure rate, 22.4%; egg reduction rate, 82.4%). Combined treatment with mebendazole and levamisole had a significantly higher efficacy against hookworm infections (cure rate, 26.1%; egg reduction rate, 88.7%) than either drug given alone. No difference in mebendazole efficacy was found in children who had been treated repeatedly compared with those who had not been treated previously. CONCLUSION The overall efficacy of mebendazole against hookworm infections after periodic chemotherapy is reduced. The efficacy of benzimidazoles in chemotherapy-based control programmes should be monitored closely. Combined treatment with mebendazole and levamisole may be useful as a tool to delay the development of benzimidazole resistance.

Effect of zinc supplementation on mortality in children aged 1–48 months: a community-based randomised placebo-controlled trial

BACKGROUND Studies from Asia have suggested that zinc supplementation can reduce morbidity and mortality in children, but evidence from malarious populations in Africa has been inconsistent. Our aim was to assess the effects of zinc supplementation on overall mortality in children in Pemba, Zanzibar. METHODS We enrolled 42,546 children aged 1-36 months, contributing a total of 56,507 child-years in a randomised, double-blind, placebo-controlled trial in Pemba, Zanzibar. Randomisation was by household. 21 274 children received daily supplementation with zinc 10 mg (5 mg in children younger than 12 months) for mean 484.7 days (SD 306.6). 21,272 received placebo. The primary endpoint was overall mortality, and analysis was by intention to treat. This study is registered as an International Standard Randomised Clinical Trial, number ISRCTN59549825. FINDINGS Overall, there was a non-significant 7% (95% CI -6% to 19%; p=0.29) reduction in the relative risk of all-cause mortality associated with zinc supplementation. INTERPRETATION We believe that a meta-analysis of all studies of mortality and morbidity, will help to make evidence-based recommendations for the role of zinc supplementation in public health policy to improve mortality, morbidity, growth, and development in young children.

Evaluation of the efficacy of pyrantel-oxantel for the treatment of soil-transmitted nematode infections.

A randomized controlled trial comparing the efficacy of pyrantel-oxantel (10 mg/kg) with mebendazole (500 mg) was performed on 1329 schoolchildren aged 6-9 years on Pemba Island in September-October 2000 to evaluate alternative single-dose drugs for regular treatment of intestinal nematode infections. Both mebendazole and pyrantel-oxantel were very effective in eliminating Ascaris lumbricoides infection, inducing cure rates of more than 96% and reducing the mean egg counts by more than 95%. Both drugs had a moderate efficacy against Trichuris trichiura infection, but pyrantel-oxantel had a higher cure rate (31.5% vs. 23.3%, P < 0.01), though the reductions in egg counts did not differ significantly and were more than 80%. Pyrantel-oxantel and mebendazole had a similar, poor efficacy in curing hookworm infections and had a moderate effect in reducing the egg counts by 67% and 68%, respectively. Pyrantel-oxantel (10 mg/kg) offers a valuable alternative to mebendazole as a single-dose treatment for the control of intestinal nematode infections in children in endemic areas of sub-Saharan Africa, due to its comparable efficacy, its low cost and its suitability for use in young children.

Short-term effects of vitamin A and antimalarial treatment on erythropoiesis in severely anemic Zanzibari preschool children

BACKGROUND The pathophysiology of anemia in coastal East Africa is complex. Impaired erythropoietin production is one possible mechanism. Plasmodium falciparum malaria has been found to blunt erythropoietin production, whereas vitamin A stimulates erythropoietin production in vitro. OBJECTIVE We investigated the 72-h effects of vitamin A and the antimalarial drug sulfadoxine pyramethamine (SP) on erythropoietin production in severely anemic (hemoglobin < or = 70 g/L) preschool children in Zanzibar, a region of known vitamin A deficiency. We hypothesized that both treatments would stimulate erythropoietin production directly, within 72 h, before a change in hemoglobin would occur. DESIGN One hundred forty-one severely anemic children were identified during the baseline assessment of a morbidity substudy of a community-based micronutrient supplementation trial. All severely anemic children were randomly assigned to receive either vitamin A (100,000 or 200,000 IU depending on age) or SP at baseline; 72 h later they received the opposite treatment plus daily hematinic syrup for 90 d. Erythropoietic and parasitic indicators were assessed at baseline and again after 72 h. RESULTS After 72 h, SP reduced the malaria parasite density (by 5029 parasites/microL; P < 0.001), CRP concentrations (by 10.6 mg/L; P = 0.001), and the proportion of children infected with malaria (by 32.4%; P < 0.001). Vitamin A reduced CRP (by 9.6 mg/L; P = 0.011), serum ferritin (by 18.1 microg/L; P = 0.042), and erythropoietin (by 194.7 mIU/mL; P = 0.011) concentrations and increased the reticulocyte production index (by 0.40; P = 0.041). CONCLUSIONS Contrary to our hypothesis, vitamin A significantly decreased erythropoietin concentration. The most important effect of both vitamin A and SP was the rapid reduction of inflammation. Vitamin A also mobilized iron from stores and stimulated the production of new erythrocytes.

Adjusting for the Acute Phase Response Is Essential to Interpret Iron Status Indicators among Young Zanzibari Children Prone to Chronic Malaria and Helminth Infections

The extent to which the acute phase response (APR) influences iron status indicators in chronic infections is not well documented. We investigated this relationship using reported recent fever and 2 acute phase proteins (APP), C-reactive protein (CRP), and alpha-1-acid glycoprotein (AGP). In a sample of 690 children matched on age and helminth infection status at baseline, we measured plasma for AGP, CRP, ferritin, transferrin receptor (TfR), and erythropoietin (EPO) and whole blood for hemoglobin (Hb) concentration, zinc protoporphyrin (ZPP), and malaria parasite density, and we obtained maternal reports of recent fever. We then examined the influence of the APR on each iron status indicator using regression analysis with Hb as the outcome variable. Ferritin was inversely related to Hb in the APR-unadjusted model. Adjusting for the APR using reported recent fever alone was not sufficient to reverse the inverse Hb-ferritin relationship. However, using CRP and/or AGP resulted in the expected positive relationship. The best fit model included reported recent fever, AGP and CRP (R(2) = 0.241; P < 0.001). The best fit Hb-ZPP, Hb-TfR, and Hb-EPO models included reported recent fever and AGP but not CRP (R(2) = 0.253, 0.310, and 0.292, respectively; P < 0.001). ZPP, TfR, and EPO were minimally influenced by the APR, whereas ferritin was immensely affected. Reported recent fever alone cannot be used as a marker for the APR. Either AGP or CRP is useful for adjusting if only 1 APP can be measured. However, AGP best predicted the APR in this population.

New insights into the transmission biology of urinary schistosomiasis in Zanzibar

A better understanding of the transmission biology of urinary schistosomiasis in Zanzibar, Tanzania was only possible after the development of molecular DNA markers for identification of Bulinus africanus group snails, the potential intermediate hosts of Schistosoma haematobium. Hitherto, identification of natural populations of B. globosus and B. nasutus was problematic and the intermediate host status and distribution of either species remained speculative. By recourse to molecular markers, snail distribution maps could be drawn, revealing an allopatric distribution and, more importantly, leading to the discovery that B. nasutus played no role in transmission. Indeed, in Unguja the area of active transmission of S. haematobium to humans is confined within the distribution of B. globosus. This strong relationship may prove useful for predicting the distribution of urinary schistosomiasis within Zanzibar and, if snail schistosome compatibilities persist, in other areas nearby, e.g. coastal Tanzania and Kenya. The transmission biology of urinary schistosomiasis in Zanzibar is reviewed, the paper reports on ongoing malacological studies in Zanzibar and Kenya and finally closes by posing the question whether medical malacology forms an essential component associated with mass-scale chemotherapy control programmes.

Early Helminth Infections Are Inversely Related to Anemia, Malnutrition, and Malaria and Are Not Associated with Inflammation in 6- to 23-Month-Old Zanzibari Children

Helminths aggravate anemia and malnutrition among school children. We studied this association in a cross-sectional study of 6- to 23-month-old Zanzibari children (N = 2322) and a sub-sample of 690 children matched on age and helminth infection status. Ascaris, hookworm, and Trichuris infections were diagnosed along with recent fever, malaria infection, mid-upper arm circumference (MUAC) and hemoglobin concentration (Hb). Alpha-1-acid glycoprotein (AGP), C-reactive protein (CRP), height, and weight were measured in the sub-sample. Infected children had higher Hb (beta = 5.44 g/L, P < 0.001) and MUAC-for-age Z score (beta = 0.30 Z, P < 0.001) compared with uninfected children after adjusting for covariates. Although helminths were not associated with inflammation, their association with Hb or MUAC-for-age Z score was modified by inflammation. Malaria-infected children were less likely to be infected with helminths (adjusted odds ratios 0.63 [95% confidence interval: 0.49, 0.81]). Non-anemic, better nourished, or non-malaria-infected children may be more exploratory of their environments and therefore increase their exposure to soil-transmitted helminths.

School enrolment in Zanzibar linked to children’s age and helminth infections

School health programmes have been identified as a cost‐effective strategy to reduce morbidity due to soil‐transmitted helminths in the school‐age population, but the low rate of school enrolment in developing countries is a major factor limiting their success.

Extending anthelminthic coverage to non-enrolled school-age children using a simple and low-cost method

School health programmes are the basis of the strategy defined by WHO to reduce morbidity due to soil‐transmitted nematodes and schistosomes in school age populations in developing countries. However, low rates of school enrolment can be a major factor limiting their success.